Heart failure in children can result from congenital or acquired injury to the myocardium. This Program Project Grant application is focused on studying the origins and treatment of heart failure in the young. The proposed studies will establish how aberrant expression of transcription factors can give rise to morphogenic anomalies that contribute to heart failure (Project 1), establish the degree to which modulation of the ROCK1 pro-apoptotic signal transduction pathway can protect against cardiomyocyte death following injuries which induce childhood heart failure (Project 2), and establish the extent to which cardioprotective cytokine pathways and hyperplastic growth programs can be manipulated to salvage at-risk myocardium and/or promote regeneration of damaged myocardial tissue following injuries which induce childhood heart failure (Project 3). The projects are thematically linked in that they examine how gene expression, cell survival and cell growth pathways are interrelated in the origins of heart failure, and furthermore how manipulation of these pathways can be exploited therapeutically. In addition to this thematic integration, the projects are technically linked in that common methodologies, approaches, and reagents will be utilized, thereby rapidly accelerating the pace of discovery. Moreover, genetic and acquired injury models and/or therapeutic interventions developed in one project will be used for proof-of-concept studies in other projects within the application, thereby accelerating the potential translation of discoveries. It should also be noted that each of the three projects represents an equal and significant contribution of effort from two established investigators having complementary skills and expertise, with one serving as Project Leader and the other as Collaborating Investigator. Thus, the Program Project Grant application will integrate the activities of six laboratories within the Cardiac Developmental Biology Program in the Herman B Wells Center for Pediatric Research with a unifying theme, thereby further enhancing the pace and productivity of research for an important and unmet clinical need, namely the study and treatment of heart failure in children.